Cancer is characterized by uncontrolled growth, proliferation, and migration of cells. Cancer is the second leading cause of death with 500,000 deaths and an estimated 1.3 million new cases in the United States in 1996. The role of signal transduction pathways contributing to cell transformation and cancer is a generally accepted concept.
Müllerian Inhibiting Substance (MIS) is a glycoprotein hormone secreted by the newly differentiating testis during the fetal period where it is responsible for regression of the Müllerian ducts in males, which would otherwise develop into the internal female reproductive tract tissues (Reviewed in (Teixeira, 2001)). However, MIS is also produced during postnatal life in both male and female gonads (Takahashi, 1986, Tran, 1987). As a member of the transforming growth factor-β (TGF-α) family, MIS signaling requires a set of membrane bound serine/threonine kinase receptors (Baarends, 1994, Clarke, 2001a, di Clemente, 1994, He, 1993, Jamin, 2002, Teixeira, 1996, Visser, 2001). After the type II receptor for MIS (MISRII) binds the MIS ligand, it recruits, phosphorylates, and activates one of three possible, activin-like kinase type I receptors (Alk2 or 3), which in turn activates the Smad 1/5/8 pathway in concert with the common Smad4. The Smad complex will translocate into the nucleus and bind to promoter regions to activate transcription of MIS-responsive genes (Massague and Wotton, 2000).
In addition to its role during male fetal development, the continuous production of this hormone in both male and females after birth indicates a function in the adult. One of the activities that has been ascribed to postnatal MIS has been as a inhibitor of tumor cell proliferation, including cells from breast (Gupta, 2005, Segev, 2000), prostate (Hoshiya, 2003, Tran, 2006), cervical (Barbie, 2003), endometrial (Renaud, 2005) and ovarian (Ha, 2000, Stephen, 2002) cancers. Since, the type II receptor for MIS is highly expressed only in the gonads and other reproductive tract organs, targeting this receptor should give rise to a selective agent and minimize side effects associated with other systemic therapy. MISRII is expressed in motor neurons (Wang, 2005) but the effect is salutary rather than inhibitory as in tumors.
However, the production of large quantities of purified, biologically active MIS sufficient to be used therapeutically is challenging. Therefore, it would be desirable to have a simple molecule that could mimic the effect of MIS by selectively activating the MISRII-mediated downstream signaling pathway.